Dyslipidemias remain a critical determinant of cardiovascular disease risk. Effective dietary and therapeutic interventions to reduce dyslipidemia, including elevated triglycerides (TGs) and high non-HDL-cholesterol exist, yet there is much variation in lipid and lipoprotein level's response to these interventions. Genetics partially explain this variation. We hypothesize that, by using improved lipid phenotyping techniques, we will be able further characterize this interindividual variation of lipids in respone to diet and drug. Recent advances in mass spectrometry-based techniques allow metabolomic characterization in large populations. Detailed and precise measurement of lipid molecular species, a field known as lipidomics, now offers an unprecedented picture of lipid metabolism. The Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN) Study provides an ideal context in which to pursue this work. GOLDN is the largest family study conducted to date that has sought to identify genetic factors that explain response to two short-term interventions, one to raise lipids (i.e., ingestion of a high-fat meal, the post-prandial lipemia (PPL) intervention and one to lower lipids (i.e., treatment with fenofibrate (FFB)). The goal of the Genomewide Association Study (GWAS) of Lipid Response to Fenofibrate and Dietary Fat (Arnett, PI, R01-HL091357) was to identify the common genetic variants that explain response to the interventions. In addition to this, GOLDN is also conducting a genome- wide epigenomics study and exome sequencing through the NIH Pharmacogenomics Research Network (PGRN). The proposed work will leverage this wealth of genomic data in the context of state-of-the-art lipidomic phenotypes, specifically phospholipids, neutral lipids, and sterols, to identify rare and common variants and epigenetic marks that determine response to GOLDN's diet and drug interventions. Specifically, we aim to: (1) Quantify pre- and post-FFB treatment/PPL response of 350 metabolites. GOLDN recruited and examined 1048 Caucasians from 186 families. Participants were given an 83% fat meal and three weeks of FFB treatment, 250 mg/d. Blood was drawn at fasting and 6-hr post ingestion and again after 3 wk of FFB treatment. Plasma from each of these time points will be analyzed with for 350 lipidomic species. PPL response (estimated as the 6-hr TG response adjusted for baseline), and fenofibrate response (estimated by the ratio of post/pre TG values) of the new lipidomic phenotypes will be calculated. Responsive and heritable metabolites will be moved forward to Aim 2. (2) Test the association of these small molecules with (a) common (GWAS) and rare (WES) variants (b) methylation at CpG sites (EWAS). (3) Replicate PPL findings in 500 subjects selected from extremes of the PPL response in the HAPI Heart Study. (4) Use induced pluripotent stem cell- derived hepatocytes to functionally validate fenofibrate response variants identified in Aim 2. If successful, GOLDN will identify novel lipidomic biomarkers to predict efficacy and adverse responses to a high-fat meal and fenofibrate treatment, leading to more personalized approaches to diet and pharmacologic treatment.